Type 2 diabetes causes cardiovascular complications including coronary artery disease. Little is known about the effects of diabetes on structural remodeling of coronary arteries. Alterations in coronary artery lumen diameter and stiffness result in reduced coronary flow reserve. Both the composition of the extracellular matrix (ECM) and vascular smooth muscle cell (VSMC) growth are key determinants of artery remodeling. Chronic hyperglycemia-induced formation of advanced glycation products (AGEs) and activation of the renin-angiotensin system (RAS) are increased in Type 2 diabetes and are related to increased oxidative stress. Preliminary data using the db/db mouse model of Type 2 diabetes indicate increased coronary artery oxidative stress, AGE accumulation and expression of AGE receptors (RAGE), AT1 receptors (AT1R) and the Nox-1 subunit of the NADPH oxidase. These molecular changes preceded increased coronary artery stiffness and inward structural remodeling. Pretreatment with the NADPH oxidase inhibitor apocynin or the AT1R blocker candesartan reduced inward vessel remodeling. Compared to Db/db controls, both coronary arteries and coronary VSMC from db/db mice have increased activation of kinase signaling cascades that are crucial for vessel remodeling. Moreover, db/db coronary VSMC exhibit increased proliferative responses to Ang II and AGE/RAGE. The overall hypothesis is that increased Ang II- and AGE-dependent oxidative stress in Type 2 diabetes alters coronary artery VSMC phenotype to increase proliferation and ECM production, leading to structural remodeling and increased stiffness. Aim 1 will utilize pharmacological inhibitors and NADPH deficient mice to establish the relative contribution of the NADPH oxidase vs. mitochondrial-induced ROS generation in diabetes-induced coronary artery remodeling. Studies in Aim 2 will use molecular and transgenic disruption of the AGE/RAGE pathway to define the molecular mechanisms by which AGE/RAGE regulate coronary artery remodeling and stiffness. Studies in Aim 3 will define the molecular interplay between RAS, AGE/RAGE, and oxidative stress in the regulation of coronary artery remodeling. A comprehensive biochemical and transgenic approach will be used to define the signaling pathways that regulate VSMC growth and ECM accumulation. PUBLIC HEALTH RELEVANCE: The proposed studies will identify unique molecular targets that contribute to Type 2 diabetes- induced coronary artery disease. Increased stiffness of coronary arteries, along with narrowing of the lumen, causes decreased blood flow to the heart during exercise and exertion, leading to myocardial infarction.